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Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Loading dose: 4,400 IU/kg at a rate of 90 mL/h over a period of 10 minutes.
- Maintenance dose: Continuous infusion of 4,400 IU/kg/h at a rate of 15 mL for 12 hours.
Off-Label Use and Dosage (Adult)
Coronary artery bypass graft occlusion
- Dosing Information
Coronary artery thrombosis
- Dosing Information
- 350,000 U/h
Deep venous thrombosis
- Intra-arterial Administration
- 50,000 units twice daily
- Intravenous Administration
- 1500-4000 units/kg/h
- Dosing Information
- 100,000-250,000 U/mL was instilled in 20 to 240-mL aliquots and reaspirated in 1 to 4 h.
- Mean duration of treatment: 6.3 days
- Intracoronary Administration
- 120,000 unit bolus doses every 5 minutes for 8 doses
- Intravenous Administration
- 3 million units given over 60 minutes
- Dosing Information
- Intrapleural 100,000 IU in 100 mL of normal saline
Prosthetic cardiac valve thrombosis
- Dosing Information
- 4500 units/kilogram/hour for 12 hours
Venous catheter occlusion
- Dosing Information
- 75,000 units/hourfor 48 hours
There is limited information regarding Off-Label Non–Guideline-Supported Use of Urokinase in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Urokinase FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
There is limited information regarding Off-Label Guideline-Supported Use of Urokinase in pediatric patients.
There is limited information regarding Off-Label Non–Guideline-Supported Use of Urokinase in pediatric patients.
The use of urokinase is contraindicated in patients with a history of hypersensitivity to the product.
Because thrombolytic therapy increases the risk of bleeding, urokinase is contraindicated in the situations listed below.
- Active internal bleeding
- Recent (e.g., within two months) cerebrovascular accident
- Recent (e.g., within two months) intracranial or intraspinal surgery
- Recent trauma including cardiopulmonary resuscitation
- Intracranial neoplasm, arteriovenous malformation, or aneurysm
- Known bleeding diatheses
- Severe uncontrolled arterial hypertension
- The risk of serious bleeding is increased with use of urokinase.
- Fatalities due to hemorrhage, including intracranial and retroperitoneal, have been reported in association with urokinase therapy.
- Concurrent administration of urokinase with other thrombolytic agents, anticoagulants, or agents inhibiting platelet function may further increase the risk of serious bleeding.
- Urokinase therapy requires careful attention to all potential bleeding sites (including catheter insertion sites, arterial and venous puncture sites, cutdown sites, and other needle puncture sites).
- Intramuscular injections and nonessential handling of the patient must be avoided during treatment with urokinase.
- Venipunctures should be performed as infrequently as possible and with care to minimize bleeding.
- Should an arterial puncture be necessary, upper extremity vessels are preferable.
- Direct pressure should be applied for at least 30 minutes, a pressure dressing applied, and the puncture site checked frequently for evidence of bleeding.
- In the following conditions, the risk of bleeding may be increased and should be weighed against the anticipated benefits:
- Recent (within 10 days) major surgery, obstetrical delivery, organ biopsy, previous puncture of non-compressible vessels
- Recent (within 10 days) serious gastrointestinal bleeding
- High likelihood of a left heart thrombus, for example, mitral stenosis with atrial fibrillation
- Subacute bacterial endocarditis
- Hemostatic defects including those secondary to severe hepatic or renal disease
- Cerebrovascular disease
- Diabetic hemorrhagic retinopathy
- Any other condition in which bleeding might constitute a significant hazard or be particularly difficult to manage because of its location
- When internal bleeding occurs, it may be more difficult to manage than that which occurs with conventional anticoagulant therapy.
- Should potentially serious spontaneous bleeding (not controllable by direct pressure) occur, the infusion of urokinase should be terminated immediately, and measures to manage the bleeding implemented.
- Serious blood loss may be managed with volume replacement, including packed red blood cells.
- Dextran should not be used. When appropriate, fresh frozen plasma and/or cryoprecipitate may be considered to reverse the bleeding tendency.
Anaphylaxis and Other Infusion Reactions
- Reactions generally occurred within one hour of beginning urokinase infusion.
- Patients who exhibit reactions should be closely monitored and appropriate therapy instituted.
- Infusion reactions generally respond to discontinuation of the infusion and/or administration of intravenous antihistamines, corticosteroids, or adrenergic agents.
- Antipyretics which inhibit platelet function (aspirin and other non-steroidal anti-inflammatory agents) may increase the risk of bleeding and should not be used for treatment of fever.
- Cholesterol embolism has been reported rarely in patients treated with all types of thrombolytic agents; the true incidence is unknown.
- This serious condition, which can be lethal, is also associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.
- Clinical features of cholesterol embolism may include livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction and rhabdomyolysis.
Product Source and Formulation with Albumin
- Urokinase is made from human neonatal kidney cells grown in tissue culture.
- Products made from human source material may contain infectious agents, such as viruses, that can cause disease.
- The risk that urokinase will transmit an infectious agent has been reduced by screening donors for prior exposure to certain viruses, by testing donors for the presence of certain current virus infections, by testing for certain viruses during manufacturing, and by inactivating and/or removing certain viruses during manufacturing.
- Despite these measures, urokinase may carry a risk of transmitting infectious agents, including those that cause Creutzfeldt-Jakob disease (CJD) or other diseases not yet known or identified; thus, the risk of transmission of infectious agents cannot be totally eliminated.
- A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is considered extremely remote.
- This product is formulated in 5% albumin, a derivative of human blood.
- Based on effective donor screening and product manufacturing processes, albumin carries an extremely remote risk for transmission of viral diseases.
- A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote.
- No cases of transmission of viral diseases or CJD have ever been identified for albumin.
Clinical Trials Experience
Bleeding is the most frequent adverse reaction associated with urokinase and can be fatal.
In controlled clinical studies using a 12-hour infusion of urokinase for the treatment of pulmonary embolism (UPET and USPET), bleeding resulting in at least a 5% decrease in hematocrit was reported in 52 of 141 urokinase-treated patients. Significant bleeding events requiring transfusion of greater than 2 units of blood were observed during the 14-day study period in 3 of 141 urokinase-treated patients in these studies. Multiple bleeding events may have occurred in an individual patient. Most bleeding occurred at sites of external incisions and vascular puncture, with lesser frequency in gastrointestinal, genitourinary, intracranial, retroperitoneal, and intramuscular sites.
Sources of Information on Adverse Reactions
There are limited well-controlled clinical studies performed using urokinase. The adverse reactions described in the following sections reflect both the clinical use of urokinase in the general population and limited controlled study data. Because post-marketing reports of adverse reactions are voluntary and the population is of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure.
Rare cases of fatal anaphylaxis have been reported. In controlled clinical trials, allergic reaction was reported in 1 of 141 patients (<1%).
Other Adverse Reactions
Other adverse events occurring in patients receiving urokinase therapy in clinical studies, regardless of causality, include myocardial infarction, recurrent pulmonary embolism, hemiplegia, stroke, decreased hematocrit, substernal pain, thrombocytopenia, and diaphoresis.
The immunogenicity of urokinase has not been studied.
Adverse reactions reported from post-marketing experience include cardiac arrest, vascular embolization (cerebral and distal) including cholesterol emboli, cerebral vascular accident, pulmonary edema, reperfusion ventricular arrhythmias and chest pain. A cause and effect relationship has not been established. Post-marketing reports of hypersensitivity reactions have included anaphylaxis (with rare reports of fatal anaphylaxis), bronchospasm, orolingual edema and urticaria. There have also been reports of other infusion reactions which have included one or more of the following: fever and/or chills/rigors, hypoxia, cyanosis, dyspnea, tachycardia, hypotension, hypertension, acidosis, back pain, vomiting, and nausea. .
- Anticoagulants and agents that alter platelet function (such as aspirin, other non-steroidal anti-inflammatory agents, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of serious bleeding.
- Administration of urokinase prior to, during, or after thrombolytic agents may increase the risk of serious bleeding.
- Because concomitant use of urokinase with agents that alter coagulation, inhibit platelet function, or are thrombolytic may further increase the potential for bleeding complications, careful monitoring for bleeding is recommended.
- The interaction of urokinase with other drugs has not been studied and is not known.
Use in Specific Populations
Pregnancy Category (FDA): B
Reproduction studies have been performed in mice and rats at doses up to 1,000 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to urokinase. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS): B1 Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.
Labor and Delivery
There is no FDA guidance on use of Urokinase during labor and delivery.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when urokinase is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of urokinase did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Urokinase should be used with caution in elderly patients.
There is no FDA guidance on the use of Urokinase with respect to specific gender populations.
There is no FDA guidance on the use of Urokinase with respect to specific racial populations.
There is no FDA guidance on the use of Urokinase in patients with renal impairment.
There is no FDA guidance on the use of Urokinase in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Urokinase in women of reproductive potentials and males.
There is no FDA guidance one the use of Urokinase in patients who are immunocompromised.
Administration and Monitoring
- Urokinase is administered using a constant infusion pump that is capable of delivering a total volume of 195 mL.
- The loading dose of urokinase admixture (4,400 international units per kilogram) should be delivered at a rate of 90 mL per hour over a period of 10 minutes.
- This is followed by a continuous infusion of 4,400 international units per kilogram per hour of urokinase at a rate of 15 mL per hour for 12 hours.
- Since some of the urokinase admixture will remain in the tubing at the end of an infusion pump delivery cycle, the following flush procedure should be performed to insure that the total dose of urokinase is administered. A solution of 0.9% Sodium *Chloride Injection, USP, or 5% Dextrose Injection, USP, approximately equal in amount to the volume of the tubing in the infusion set should be administered via the pump to flush the urokinase admixture from the entire length of the infusion set. The pump should be set to administer the flush solution at the continuous rate of 15 mL per hour.
- No other drug products/solutions may be administered in the same line with urokinasec
- The Dose Preparation-Pulmonary Embolism chart is a guidance tool/aid provided for the convenience of the practitioner and may not be complete for every patient.
- Urokinase contains no preservatives. Do not reconstitute until immediately before use. *Any unused portion of the reconstituted material should be discarded.
- Reconstitute urokinase by aseptically adding 5 mL of Sterile Water for Injection, USP, without preservatives, to the vial. DO NOT USE Bacteriostatic Water for Injection, USP.
- After reconstitution, the drug product will contain 50,000 international units per milliliter.
- After reconstituting, visually inspect each vial of urokinase for discoloration and for the presence of particulate material. The solution should be pale and straw-colored; highly colored solutions should not be used. Thin translucent filaments may occasionally occur in reconstituted urokinase vials, but do not indicate any decrease in potency of this product. To minimize formation of filaments, avoid shaking the vial during reconstitution. Roll and tilt the vial to enhance reconstitution. The solution may be terminally filtered, for example, through a 0.45 micron or smaller cellulose membrane filter.
- No other medication should be added to this solution.
- Prior to infusing, dilute the reconstituted urokinase with 0.9% sodium chloride injection, USP or 5% Dextrose injection, USP.
The following Dose Preparation-Pulmonary Embolism chart may be used as an aid in the preparation of urokinase for administration. For administration directions, see next section.
Anticoagulation After Terminating Urokinase Treatment
After infusing urokinase, anticoagulation treatment is recommended to prevent recurrent thrombosis. Do not begin anticoagulation until the aPTT has decreased to less than twice the normal control value. If heparin is used, do not administer a loading dose of heparin. Treatment should be followed by oral anticoagulants.
Urokinase should be used in hospitals where the recommended diagnostic and monitoring techniques are available.
The clinical response and vital signs should be observed frequently during and following urokinase infusion. Blood pressure should not be taken in the lower extremities to avoid dislodgement of possible deep vein thrombi.
Before beginning thrombolytic therapy, obtain a hematocrit, platelet count, and an activated partial thromboplastin time (aPTT). If heparin has been given, it should be discontinued and the aPTT should be less than twice the normal control value before thrombolytic therapy is started.
Following intravenous infusion of urokinase, before (re)instituting anticoagulants, the aPTT should be less than twice the normal control value.
Results of coagulation tests and measures of fibrinolytic activity do not reliably predict either efficacy or risk of bleeding for patients receiving urokinase.
There is limited information regarding the compatibility of Urokinase and IV administrations.
There is limited information regarding Urokinase overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
|Systematic (IUPAC) name|
|Mol. mass||31126.5 g/mol|
Mechanism of Action
Urokinase is an enzyme (protein) produced by the kidney, and found in the urine. There are two forms of urokinase which differ in molecular weight but have similar clinical effects. Urokinase is the low molecular weight form. urokinase acts on the endogenous fibrinolytic system. It converts plasminogen to the enzyme plasmin. Plasmin degrades fibrin clots as well as fibrinogen and some other plasma proteins.
The principal active ingredient of urokinase is the low molecular weight form of urokinase, and consists of an A chain of 2,000 daltons linked by a sulfhydryl bond to a B chain of 30,400 daltons.
Intravenous infusion of urokinase in doses recommended for lysis of pulmonary embolism is followed by increased fibrinolytic activity in the circulation. This effect disappears within a few hours after discontinuation, but a decrease in plasma levels of fibrinogen and plasminogen and an increase in the amount of circulating fibrin and fibrinogen degradation products may persist for 12-24 hours.2 There is a lack of correlation between embolus resolution and changes in coagulation and fibrinolytic assay results.
Information about the pharmacokinetic properties in man is limited. Urokinase administered by intravenous infusion is rapidly cleared by the liver with an elimination half-life for biologic activity of 12.6 ± 6.2 minutes and a distribution volume of 11.5 L. Small fractions of the administered dose are excreted in bile and urine. Although the pharmacokinetics of exogenously administered urokinase have not been characterized in patients with hepatic impairment, endogenous urokinase-type plasminogen activator plasma levels are elevated 2- to 4-fold in patients with moderate to severe cirrhosis.1 Thus, reduced urokinase clearance in patients with hepatic impairment might be expected.
Adequate data are not available on the long-term potential for carcinogenicity in animals or humans.
There is limited information regarding Urokinase Clinical Studies in the drug label.
Urokinase is supplied as a sterile lyophilized preparation (NDC 24430-1003-1). Each vial contains 250,000 international units urokinase activity, 25 mg mannitol, 250 mg Albumin (Human), and 50 mg sodium chloride.
Refrigerate urokinase powder at 2° to 8°C (36° to 46°F)
Package and Label Display Panel
Patient Counseling Information
There is limited information regarding Urokinase Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Urokinase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Look-Alike Drug Names
There is limited information regarding Urokinase Look-Alike Drug Names in the drug label.
The contents of this FDA label are provided by the National Library of Medicine.
- K. Mehta & E. Schechter (1998). "Long-term angiographic follow-up of occluded saphenous bypass grafts treated with prolonged urokinase infusion". Catheterization and cardiovascular diagnosis. 44 (3): 291–296. PMID 9676798. Unknown parameter
- J. R. Hartmann, L. S. McKeever, W. W. O'Neill, C. J. White, P. L. Whitlow, P. S. Gilmore, A. J. Doorey, J. P. Galichia & E. L. Enger (1996). "Recanalization of Chronically Occluded Aortocoronary Saphenous Vein Bypass Grafts With Long-Term, Low Dose Direct Infusion of Urokinase (ROBUST): a serial trial". Journal of the American College of Cardiology. 27 (1): 60–66. PMID 8522711. doi:10.1016/0735-1097(95)00448-3. Unknown parameter
- P. S. Teirstein, J. T. 3rd Mann, P. E. Jr Cundey, E. Schechter, W. C. Jacobs, C. L. Grines, D. J. Stagaman, A. J. Lansky, M. A. Hultquist, B. A. Kusnick, R. R. Heuser, H. D. Kleinert & J. Popma (1999). "Low- versus high-dose recombinant urokinase for the treatment of chronic saphenous vein graft occlusion". The American journal of cardiology. 83 (12): 1623–1628. PMID 10392865. Unknown parameter
- S. K. Garg & K. S. Yadav (1999). "Developing venous gangrene in deep vein thrombosis: intraarterial low-dose burst therapy with urokinase--case reports". Angiology. 50 (2): 157–162. PMID 10063948. Unknown parameter
- A. D'Angelo & P. M. Mannucci (1984). "Outcome of treatment of deep-vein thrombosis with urokinase: relationship to dosage, duration of therapy, age of the thrombus and laboratory changes". Thrombosis and haemostasis. 51 (2): 236–239. PMID 6740556. Unknown parameter
- J. S. Moulton, R. E. Benkert, K. H. Weisiger & J. A. Chambers (1995). "Treatment of complicated pleural fluid collections with image-guided drainage and intracavitary urokinase". Chest. 108 (5): 1252–1259. PMID 7587425. Unknown parameter
- H. Kambara, K. Kammatsuse, M. Nobuyoshi, K. Kodama, H. Sato, S. Sasayama, N. Kajiwara, M. Nakashima & C. Kawai (1987). "Randomized double-blind trial of intracoronary urokinase for acute myocardial infarction: multicenter study". Japanese circulation journal. 51 (9): 1072–1076. PMID 3320390. Unknown parameter
- T. C. Wall, H. R. 3rd Phillips, R. S. Stack, S. Mantell, L. Aronson, J. Boswick, K. Sigmon, M. DiMeo, D. Chaplin & D. Whitcomb (1990). "Results of high dose intravenous urokinase for acute myocardial infarction". The American journal of cardiology. 65 (3): 124–131. PMID 2296881. Unknown parameter
- D. Bouros, S. Schiza, N. Tzanakis, G. Chalkiadakis, J. Drositis & N. Siafakas (1999). "Intrapleural urokinase versus normal saline in the treatment of complicated parapneumonic effusions and empyema. A randomized, double-blind study". American journal of respiratory and critical care medicine. 159 (1): 37–42. PMID 9872815. doi:10.1164/ajrccm.159.1.9803094. Unknown parameter
- L. D. Ledain, J. P. Ohayon, J. P. Colle, F. M. Lorient-Roudaut, R. P. Roudaut & P. M. Besse (1986). "Acute thrombotic obstruction with disc valve prostheses: diagnostic considerations and fibrinolytic treatment". Journal of the American College of Cardiology. 7 (4): 743–751. PMID 3958331. Unknown parameter
- J. Schindler, R. D. Bona, H. H. Chen, J. M. Feingold, R. L. Edwards, P. J. Tutschka & S. Bilgrami (1999). "Regional thrombolysis with urokinase for central venous catheter-related thrombosis in patients undergoing high-dose chemotherapy with autologous blood stem cell rescue". Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 5 (1): 25–29. PMID 10725979. Unknown parameter